I M B O A R D REVIEW D A V I D L. L O N G W O R T H , M D , J A M E S K. STOLLER, M D , EDITORS

A R L E N E LOBO, M D Department of Pulmonary and Critical Care Medicine, Cleveland Clinic

R A E D A. D W E I K , M D Department of Pulmonary and Critical Care Medicine, Cleveland Clinic

A 5 7 ̂ y earmold woman with pulmonary infiltrates and eosinophilia

57-YEAR-OLD W O M A N with a history of asthma for many years presents because

of fever, dyspnea, and cough (productive of yellow sputum), lasting several weeks. She also reports generalized weakness, fatigue, anorexia, and night sweats for the same dura-tion. S h e has never smoked. S h e was immunocompetent, and a purified protein derivative (PPD) skin test was negative. She had been treated with several oral and intra-venous antibiotics without improvement.

Physica l e x a m i n a t i o n , d i a g n o s t i c t e s t s T h e patient is afebrile and in mild respiratory distress. Lung auscultation reveals bilateral scattered wheezes. Otherwise, the physical examination is normal.

O n presentation, chest radiography demonstrates bilateral peripheral infiltrates with a small right pleural effusion (FIGURE 1). Her complete blood count is as follows:

• Hemoglobin 10.0 g/dL • Hematocrit 3 0 % • Platelet count 389 x lO^/L • Whi te blood cell count 4 .94 x 109/L

(neutrophils 43%, lymphocytes 15%, eosinophils 3 8 % ) .

• CAUSES OF P U L M O N A R Y INFILTRATES W I T H E O S I N O P H I L I A

1 • • • • •

W h a t is the diagnosis?

Acute eosinophilic pneumonia Chronic eosinophilic pneumonia Allergic bronchopulmonary aspergillosis Churg-Strauss syndrome Fungal pneumonia

All the disease processes listed above can

FIGURE 1. P r e s e n t i n g p o s t e r o a n t e r i o r chest r a d i o g r a p h . N o t i c e t h e b i l a t e r a l p e r i p h e r a l a l v e o l a r i n f i l t r a t e s i n v o l v i n g t h e u p p e r l u n g z o n e s p r e d o m i n a n t l y o n t h e l e f t side.

cause pulmonary infiltrates with peripheral eosinophilia (arbitrarily defined as greater than 6 % eosinophils on the differential white blood cell count).

• D I F F E R E N T I A L D I A G N O S I S : E O S I N O P H I L I N V O L V E M E N T IN L U N G DISEASE

T A B L E 1 lists common causes of the syndrome of pulmonary infiltrates with eosinophilia. O f note: These are distinct disorders that gener-ally have little clinical relationship to one another except for the presence of eosinophils. In some (ie, those in the top part

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I M B O A R D R E V I E W L O B O A N O D W E I K

Chronic and acute eosinophilic pneumonia are two completely distinct diseases

Differential diagnosis of pulmonary infiltrates with eosinophilia EOSINOPHILIC LUNG DISEASES

Simple pulmonary eosinophilia (Loffler syndrome) Parasitic infection Drug reaction Toxins, allergins

Acute eosinophilic pneumonia Chronic eosinophilic pneumonia Hypereosinophilic syndrome Pulmonary eosinophil ia w i t h asthma

Allergic bronchopulmonary aspergillosis Tropical pulmonary eosinophil ia Vasculitis

Churg-Strauss syndrome

LUNG DISEASES SOMETIMES ASSOCIATED WITH EOSINOPHILS

Fungal infection Mycobacterial infection Malignancy Idiopathic pulmonary fibrosis

of TABLE 1), eosinophila is part of the definition of the disease or is thought to be of patho-genetic importance.

In the other lung diseases listed in TABLE 1,

eosinophil involvement is variable, and eosinophils are not considered an integral part of the disease process.

S i m p l e p u l m o n a r y e o s i n o p h i l i a Simple pulmonary eosinophilia (Loffler syn-drome) is characterized by transient pul-monary infiltrates with peripheral eosinophil-ia and minimal or no pulmonary symptoms. Loffler syndrome is usually secondary to para-sitic infection (eg, Ascaris lumbricoid.es), aller-gens, or drugs or toxins (eg, sulfonamides). Acute and chronic eosinophilic pneumonias are discussed in more detail below.

A c u t e eos inoph i l i c p n e u m o n i a Acute eosinophilic pneumonia must be dif-ferentiated from chronic eosinophilic pneu-monia. Although the nomenclature is simi-lar, they are two completely different dis-eases.

Patients with acute eosinophilic pneumo-nia may be of any age and may present with an acute febrile illness of 1 to 5 days' duration accompanied by myalgias, pleuritic chest pain, and hypoxemic respiratory failure, often requiring mechanical ventilation. T h e earliest chest radiographic findings show only subtle amounts of interstitial infiltrate, often with Kerley B lines. This is followed within hours to a few days by extensive mixed alveolar and interstitial infiltrates involving all lobes. Computed tomography ( C T ) of the chest usu-ally shows diffuse parenchymal alveolar infil-trates, pleural effusions, and pronounced sep-tal markings, but no adenopathy.

The percentage of eosinophils is usually normal in the peripheral blood. In contrast, it is elevated in the bronchoalveolar lavage fluid. The percentages of lymphocytes and neutrophils in lavage fluid are also elevated. Lung biopsy reveals eosinophils and edema within the alveolar space, the bronchial walls, and the interstitial space.

Pulmonary function testing in the acute phase shows a low diffusing capacity and a restrictive pattern. After treatment, pul-monary function tests usually return to nor-mal.

Patients with acute eosinophilic pneumo-nia respond rapidly to high doses of corticos-teroids, usually within 24 to 48 hours. A com-monly used regimen is 60 to 125 mg of methyl-prednisolone intravenously every 6 hours until respiratory failure resolves, usually in 1 to 3 days, followed by oral prednisone 40 to 60 mg/day tapered over the next 2 to 4 weeks. Unlike patients with chronic eosinophilic pneumonia, patients with acute eosinophilic pneumonia do not relapse after discontinua-tion of corticosteroids.

Chron ic eos inoph i l i c p n e u m o n i a Patients with chronic eosinophilic pneumonia are often in their 50s, and women outnumber men by 2 to 1. The onset of symptoms is often insidious over several weeks or months. Common symptoms include cough (90%), fever (87%), dyspnea (57%) , and weight loss ( 5 7 % ) . Other symptoms include malaise, wheezing, night sweats, sputum production, myalgias, and chest pain. Asthma is present in about 5 0 % of cases.

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Peripheral blood eosinophilia (> 6 % ) is usually mild or moderate. Eosinophils can be found in the sputum in about half of the patients. Serum IgE levels are increased in two thirds of patients, and rheumatoid factor or immune complexes may also be present. The erythrocyte sedimentation rate is usually ele-vated, and peripheral blood thrombocytosis has been reported.

Pulmonary function tests can be normal in mild cases, but usually show restrictive defects with a reduction in diffusing capacity. Obstructive defects are most likely due to con-current asthma. All patients have an increased alveolar-arterial oxygen gradient.

Chest radiography demonstrates peripher-al-based infiltrates located in the outer two thirds of the lung fields in about 6 5 % of patients. A chest C T scan (FIGURE 2) shows peripheral air space disease. Bronchoalveolar lavage fluid demonstrates high percentages of eosinophils (> 25%) in the acute stage of chronic eosinophilic pneumonia.

Hypereosinophi l ic syndrome Hypereosinophilic syndrome is a rare and often fatal disorder defined as an eosinophil count of 1.5 x 109/L for at least 6 months. Hypereosinophilic syndrome can involve any organ system, but the major source of mortal-ity and morbidity is cardiac involvement. T h e lungs are involved in 4 0 % of patients.

Allergic bronchopulmonary aspergil losis Allergic bronchopulmonary aspergillosis is an asthmatic syndrome that also occurs in 10% of patients with cystic fibrosis. Diagnostic crite-ria include asthma, eosinophilia, immediate skin sensitivity to Aspergillus fumigatus anti-gen, and elevated immunoglobulin E levels. Chest radiographs in allergic bronchopul-monary aspergillosis may reveal the classic "gloved finger" infiltrates that suggest bronchiectasis and mucoid impaction.

Tropical pu lmonary eosinophi l ia Tropical pulmonary eosinophilia is seen in areas of endemic filariasis and is thought to be secondary to infection with the human filari-al species Wuchereria bancrofti or Brugia malayi. For a more detailed discussion of the clinical features of these entities, the reader is referred

F I G U R E 2 . T h e per iphera l na tu re of t h e inf i l t rates in chron-ic eosinophil ic p n e u m o n i a can be wel l apprec ia ted o n this CT scan of t h e chest (same pa t i en t as in F I G U R E 1 ) . A CT scan o f t h e chest, however , is ne i ther necessary nor suff ic ient to m a k e t h e diagnosis of chronic eosinophil ic p n e u m o n i a .

to the excellent reviews on the topic given in the reading list at the end of this article.

Churg-Strauss syndrome Churg-Strauss syndrome, also known as aller-gic angiitis and granulomatosis, is a rare syn-drome of asthma, eosinophilia, and systemic vasculitis. Churg-Strauss syndrome involves the small arteries and veins and must be dif-ferentiated from polyarteritis nodosa, which involves the medium-size vessels and is not associated with asthma or eosinophilia.

• HOW TO PROCEED

The patient's chest radiograph (FIGURE 1) has the classic features of chronic eosinophilic pneumonia, which is often described as the "photographic negative of pulmonary edema" and results from the peripheral nature of the infiltrates. Although this patient's clinical presentation combined with the radiographic features strongly suggests chronic eosinophilic pneumonia, other causes of the syndrome of pulmonary infiltrates with eosinophilia (par-ticularly infection) must be excluded before initiating therapy. Since many entities that can cause this syndrome (TABLE 1) can have nonspecific clinical presentations, the clinical picture alone is not always sufficient to reach a final diagnosis without further testing.

Chronic eosinophilic pneumonia is the "photographic negative of pulmonary edema"

337 CLEVELAND CLINIC JOURNAL OF MEDICINE V O L U M E 66 • NUMBER 6 JUNE 1 9 9 9

IM BOARD REVIEW LOBO AND DWEIK

« * M MHXif f - *?

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FIGURE 3 . Transbronchial lung biopsy specimen demon-strating an acute and organizing pneumonia w i th intense eosinophilic infiltrate.

with 1% neutrophils, 5 % lymphocytes, 2 % monocytes, 4 % macrophages, and 8 7 % eosinophils (normal < 1%) . Transbronchial biopsy demonstrated an eosinophilic infiltrate ( F I G U R E 3 ) . Stains and cultures for bacteria, tuberculosis, and fungi in the bronchoalveolar lavage fluid were all negative. Stool tests for ova and parasites were repeatedly negative.

T h e high level of eosinophilia in the lavage fluid and the presence of numerous eosinophils on transbronchial biopsy, com-bined with the clinical and radiographic fea-tures, strongly suggests chronic eosinophilic pneumonia in this patient.

• TREATMENT OF CHRONIC EOSINOPHILIC PNEUMONIA

What is the treatment of choice?

Relapses are common if corticosteroids are stopped too soon

• • •

SELECTING A MINIMALLY INVASIVE, HIGH-YIELD DIAGNOSTIC METHOD

| What would you do next to reach a diag-> nosis?

Computed tomography ( C T ) of the chest Open lung biopsy Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy

A C T scan of the chest may help better define the infiltrates and may indicate whether lym-phadenopathy is present, but it will not help to make a firm diagnosis.

Although open lung biopsy is the "gold standard" and may have the highest yield for making the diagnosis, it is invasive and carries the risk of a surgical procedure.

Flexible bronchoscopy with bronchoalve-olar lavage and transbronchial biopsy is the procedure of choice because it is safe and min-imally invasive and can have a reasonably high diagnostic yield, especially by effectively excluding infectious etiologies.

• CASE CONTINUED: BRONCHOSCOPE FINDINGS

Bronchoscopy was performed in this patient, and the bronchoalveolar lavage fluid revealed a total white blood cell count of 2.25 x 109/L

• Antibiotics • Antifungals • Corticosteroids

Treatment of chronic eosinophilic pneumo-nia consists of systemic (oral or intravenous) corticosteroids. Although the mechanism of action of corticosteroids is not fully under-stood, they lead to rapid sequestration of eosinophils within the circulation and may block eosinophil production by the bone marrow. Corticosteroids can also inhibit eosinophil adherence and chemotaxis and reduce eosinophil survival. Commonly used doses of steroids are 40 to 80 mg of pred-nisone daily tapered slowly over 6 to 12 months.

There is a high relapse rate if steroid ther-apy is discontinued in the first 6 months, and some patients require steroid therapy indefi-nitely.

Patient's t reatment course Our patient was treated with prednisone 40 mg twice a day for a week, and her symptoms improved markedly. She was prescribed main-tenance therapy consisting of prednisone 40 mg daily, with complete resolution of her peripheral eosinophilia and pulmonary infil-trates (FIGURE 4) . Steroids were tapered slowly over 6 months, with no recurrence of the symptoms at 1 year.

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F I G U R E 4 . Chest r a d i o g r a p h f r o m p a t i e n t in FIGURES 1 a n d 3 a f t e r 2 m o n t h s o f ora l cor-t i cos te ro id therapy . N o t i c e t h e c o m p l e t e r e s o l u t i o n of the in f i l t ra tes seen in FIGURE 1.

• W H E N TO CONSIDER A D I A G N O S I S OF CHRONIC EOSINOPHIL IC P N E U M O N I A

Although chronic eosinophilic pneumonia is uncommon, it is important to consider it in the differential diagnosis of pulmonary infil-trates, especially in patients who do not improve with antibiotic therapy. Early appro-priate diagnostic evaluation and proper treat-ment (as outlined above) are important to achieve a good outcome. S3

• SUGGESTED R E A D I N G Allen JN, Davis WB. Eosinophilic lung diseases. Am J Respir Crit Care Med 1994; 150:1423-1438. Meeker DR Pulmonary infiltrates and eosinophilia revisited. Cleve Cl in ] Med 1939; 56:199-211. Naughton M, Fahy J, FitzGerald MX. Chronic eosinophilic pneumonia: a long-term follow-up of 12 patients. Chest 1993; 103:162-165. Tazelaar HD, Llnz LI, Colby TV, Meyers JL, Limper AH. Acute eosinophilic pneumonia: findings in nine patients. Am J Respir Crit Care Med 1997; 155:296-302.

ADDRESS: Raed A. Dweik, MD, Department of Pulmonary and Critical Care Medicine, A90, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: dweikr@ccf.org.

• CME ANSWERS Answers to the CREDIT TEST on page 383 of this issue 1 E 2 D 3 C 4 E 5 C 6 B 7 D 8 E 9 E 1 0 B 11 D

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